Growth factors of the Epidermal Growth Factor family play pivotal roles in development of the nervous system and the cardiovascular system. Interest in the functions of these hormones and receptors in the mammary gland is driven by the important of epidermal growth factor receptor and the related receptor ErbB-2 in breast cancer and other carcinomas. In contrast, the related growth factors called neuregulins and their receptor ErbB-4 may be linked more tightly to terminal differentiation of the mammary gland, and may antagonize proliferation. We will test these hypotheses directly using mouse and tissue culture models. Aim 1. ErbB-4 will be selective disrupted in the mammary gland using a floxed ErbB-4 gene activated by Cre recombinase expressed in the mammary gland. The effects on mammary development and responsiveness to prototype EGF family ligands will be determined. Aim 2 will test the hypothesis that ErbB-4 antagonize mammary carcinogenesis by determining the effect of ErbB-4 disruption on kinetics of tumors induced by the MMTV-NEU transgene. Aim 4. ErbB-4 specific substrates will be sought, in order to link differences in biological response associated with this receptor to differences in regulation of downstream signaling proteins. Health relatedness. The results will suggest whether ErbB-4 signaling portends a favorable prognosis and activation of ErbB-4-regulated signaling pathways would be beneficial to breast cancer patients. Moreover, since ErbB-2 is a co-receptor that works together with ErbB-4, therapeutic antagonism of ErbB-2 may be harmful in situations where ErbB-4 signaling in prominent. The import of this work will extend beyond cancer research. Aim 3 will explore general areas of ErbB4 signaling. ErbB4 functions in cardiac development suggests that ErbB-4 regulated pathways may be important in developing treatments for multiple sclerosis and nerve damage.